The tumor-associated antigen PRAME (PReferentially expressed Antigen in MElanoma cells) was originally identified as an antigen recognized by cytotoxic T lymphocytes capable of lysing melanoma cells (Ikeda et al., Immunity. 1997; 6:199-208.) Although the tumor antigen PRAME is known to be overexpressed in a wide variety of human cancers, its molecular function has remained unclear until recently. PRAME was recently identified as a dominant repressor of RAR (retinoic acid receptor) signalling. PRAME was shown to bind RAR in the presence of RA, preventing ligand-induced receptor activation and target gene transcription through recruitment of Polycomb proteins. PRAME was shown to be present at RAR target promoters and inhibited RA-induced differentiation, growth arrest, and apoptosis. Conversely, inhibition of PRAME expression by RNA interference in RA-resistant human melanoma restored RAR signalling and reinstated sensitivity to the antiproliferative effects of RA in vitro and in vivo. (Epping et al., Cell. 2005; 122(6): 835-47). Overexpression of PRAME, as is frequently observed in human malignancies, may provide tumor cells growth and survival advantages by antagonizing RAR signalling.
PRAME has in fact been found to be overexpressed in a broad array of solid tumors and 30% of acute leukaemia's, whereas normal tissue expression is confined to the testis, endometrium and at very low levels in ovaries and adrenals. It is an established tumor antigen and its potential application as target for immunotherapies is well documented in art, as discussed in U.S. Pat. No. 5,830,753, U.S. Pat. No. 6,297,050, U.S. Pat. No. 6,339,149, EP 0783511 B1, WO 01/52612 and US 2005/0221440 A1. Despite many publications that indicate the potential of PRAME as a tumor antigen and attractive candidate target of eliciting anti-tumor cell immune responses and preparing anti-tumor vaccines, little data are available that substantiate the natural preservation of the PRAME derived peptides and epitopes, neither were data available showing the immunogenicity of these epitopes, which is needed to establish an effective anti-tumor T-cell response. The current invention addresses this problem and provides improved PRAME derived peptides comprising newly identified MHC class I and II epitopes and compositions comprising these peptides.